In a population-based study, we examined the relationship between the risk of myocardial infarction (MI) among young women and plasma total homocysteine (tHCY), folate, vitamin B-12, and a common cytosine to thymine (T) polymorphism in the gene for 5,10-methylenetetrahydrofolate reductase (MTHFR). In-person interviews and non-fasting blood samples were obtained from 79 women <45 years old diagnosed with MI and 386 demographically similar control subjects living in western Washington state between 1991 and 1995. Compared with control subjects, case patients had higher mean tHcy concentrations (13.4 5.2 versus 11.1 4.4 mol/L, P=.0004) and lower mean folate concentrations (12.4 13.4 versus 16.1 12.2 nmol/L, P=0.18). There was no difference in vitamin B-12 concentrations between case patients and control subjects (346.8 188.4 versus 349.7 132.4 pmol/L, P=.90). After adjusting for cardiovascular risk factors, we found that women with tHCY 15.6 mol/L were at approximately twice the risk of MI as women with tHCY <10.0 mol/L (OR, 2.3; 95% CI, 0.94 to 5.64). Women with folate 8.39 nmol/L had an ~50% lower risk of MI than women with folate <5.27 nmol/L (OR, 0.54; 95% CI, 0.23 to 1.28). There is no association with vitamin B-12 concentration. Among control subjects, 12.7% were homozygous for the MTHFR T677 allele, and these women had higher plasma tHCY and lower plasma folate than women with other genotypes. Ten percent of case patients were homozygous for the T677 allele, and there was no association of homozygosity for T677 with MI risk. These data support the hypothesis that elevated plasma tHCY and low plasma folate are risk factors for MI among young women. Although homozygosity for MTHFR T677 is related to increased plasma tHCY and low plasma folate, this genetic characteristic is not a risk factor for MI in this population.